ABSTRACT
Further lead optimization efforts on previously described 1,2,3,4,10,10a-hexahydro-1H-pyrazino[1,2-a]indoles led to the new class of 5,5a,6,7,8,9-hexahydro-pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazines culminating in the discovery of (5aR,9R)-2-[(cyclopropylmethoxy)methyl]-5,5a,6,7,8,9-hexahydro-9-methyl-pyrido[3', 2':4,5]pyrrolo[1,2-a]pyrazine 18 as a potent, full 5-HT(2C) receptor agonist with an outstanding selectivity profile and excellent hERG and phospholipidosis properties.
Subject(s)
Pyrazines/chemistry , Pyrazines/pharmacology , Pyrroles/chemistry , Serotonin 5-HT2 Receptor Agonists , Animals , CHO Cells , Cricetinae , Humans , Hydroxylation , Molecular Structure , Phospholipids/pharmacology , Pyrazines/chemical synthesis , Receptor, Serotonin, 5-HT2C/genetics , Receptor, Serotonin, 5-HT2C/metabolism , Structure-Activity RelationshipABSTRACT
Synthesis and evaluation of the activity of new 4-methyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indoles as 5-HT(2C) receptor agonists are described. Appropriately substituted, several analogs displayed selectivity against the other 5-HT(2) receptor subtypes of 1 order of magnitude or more. Selectivity was improved for several compounds versus the lead 1, increasing the therapeutic interest in this series of 5-HT(2C) receptor agonists.
Subject(s)
Eating/drug effects , Serotonin 5-HT2 Receptor Agonists , Serotonin Receptor Agonists/pharmacology , Animals , Indoles/chemical synthesis , Indoles/pharmacology , Injections, Subcutaneous , Pyrazines/chemical synthesis , Pyrazines/pharmacology , Pyridines/chemical synthesis , Pyridines/pharmacology , Rats , Rats, Wistar , Serotonin Receptor Agonists/chemical synthesis , Structure-Activity RelationshipABSTRACT
Ro 63-9141 is a new member of the pyrrolidinone-3-ylidenemethyl cephem series of cephalosporins. Its antibacterial spectrum was evaluated against significant gram-positive and gram-negative pathogens in comparison with those of reference drugs, including cefotaxime, cefepime, meropenem, and ciprofloxacin. Ro 63-9141 showed high antibacterial in vitro activity against gram-positive bacteria except ampicillin-resistant enterococci, particularly vancomycin-resistant strains of Enterococcus faecium. Its MIC at which 90% of the isolates tested were inhibited (MIC(90)) for methicillin-resistant Staphylococcus aureus (MRSA) was 4 microg/ml. Ro 63-9141 was bactericidal against MRSA. Development of resistance to the new compound in MRSA was not observed. Ro 63-9141 was more potent than cefotaxime against penicillin-resistant Streptococcus pneumoniae (MIC(90) = 2 microg/ml). It was active against ceftazidime-susceptible strains of Pseudomonas aeruginosa and against Enterobacteriaceae except Proteus vulgaris and some isolates producing extended-spectrum beta-lactamases. The basis for the antibacterial spectrum of Ro 63-9141 lies in its affinity to essential penicillin-binding proteins, including PBP 2' of MRSA, and its stability towards beta-lactamases. The in vivo findings were in accordance with the in vitro susceptibilities of the pathogens. These data suggest the potential utility of Ro 63-9141 for the therapy of infections caused by susceptible pathogens, including MRSA. Since insufficient solubility of Ro 63-9141 itself precludes parenteral administration in humans, a water-soluble prodrug, Ro 65-5788, is considered for development.
Subject(s)
Bacterial Proteins , Cephalosporins/pharmacology , Hexosyltransferases , Methicillin Resistance/physiology , Peptidyl Transferases , Staphylococcus aureus/drug effects , Abscess/drug therapy , Animals , Carrier Proteins/antagonists & inhibitors , Cephalosporins/metabolism , Cephalosporins/therapeutic use , Disease Models, Animal , Enzyme Stability , Mice , Microbial Sensitivity Tests , Muramoylpentapeptide Carboxypeptidase/antagonists & inhibitors , Penicillin-Binding Proteins , Sepsis/drug therapy , Staphylococcus aureus/enzymology , Staphylococcus aureus/metabolism , Substrate Specificity , beta-Lactamases/metabolismABSTRACT
The synthesis and structure-activity relationships of a new class of vinylcephalosporins substituted with a lactamyl residue are described. These compounds show excellent activity against enterococci and retain the broad spectrum activity of third-generation cephalosporins such as ceftriaxone.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Cephalosporins/chemical synthesis , Cephalosporins/pharmacology , Enterococcus/drug effects , Staphylococcus/drug effects , Streptococcus pneumoniae/drug effects , Anti-Bacterial Agents/chemistry , Cephalosporins/chemistry , Microbial Sensitivity Tests , Spectrum Analysis , Structure-Activity RelationshipABSTRACT
Cyclothialidine is a new, potent DNA gyrase inhibitor isolated from Streptomyces filipinensis. However, it exhibits hardly any growth-inhibitory activity against intact bacterial cells. To explore its potential with regard to the development of a new type of antibacterial, a flexible synthetic route was worked out (i) to investigate the structural requirements for DNA gyrase inhibition and (ii) to search for congeners exerting antibacterial activity. The structure of cyclothialidine was confirmed by total synthesis. Marked DNA gyrase inhibitory activity was found for a number of analogs, a common feature of them being the bicyclic 12-membered lactone bearing one phenolic hydroxy group. Congeners of cyclothialidine were found to exhibit a moderate, but broad-spectrum, in vitro activity against Gram-positive bacteria. Therefore, the DNA gyrase inhibitory principle contained in cyclothialidine can be considered as the basis for a new class of antibacterial agents.
